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Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.

التفاصيل البيبلوغرافية
العنوان: Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial.
المؤلفون: Sutharsan S; Department of Pulmonary Medicine, Division of Cystic Fibrosis, University Medicine Essen-Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany. Electronic address: sivagurunathan.sutharsan@rlk.uk-essen.de., McKone EF; National Referral Center for Adult Cystic Fibrosis, St Vincent's University Hospital, and University College Dublin, Dublin, Ireland., Downey DG; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK., Duckers J; All Wales Adult Cystic Fibrosis Centre, University Hospital Llandough, Cardiff, UK., MacGregor G; Department of Respiratory Medicine, Queen Elizabeth University Hospital, Glasgow, UK., Tullis E; St Michael's Hospital, University of Toronto, Toronto, ON, Canada., Van Braeckel E; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium., Wainwright CE; Queensland Children's Hospital, University of Queensland, Brisbane, QLD, Australia., Watson D; Adult Cystic Fibrosis Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK., Ahluwalia N; Vertex Pharmaceuticals, Boston, MA, USA., Bruinsma BG; Vertex Pharmaceuticals, Boston, MA, USA., Harris C; Vertex Pharmaceuticals, Boston, MA, USA., Lam AP; Vertex Pharmaceuticals, Boston, MA, USA., Lou Y; Vertex Pharmaceuticals, Boston, MA, USA., Moskowitz SM; Vertex Pharmaceuticals, Boston, MA, USA., Tian S; Vertex Pharmaceuticals, Boston, MA, USA., Yuan J; Vertex Pharmaceuticals, Boston, MA, USA., Waltz D; Vertex Pharmaceuticals, Boston, MA, USA., Mall MA; Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany; German Center for Lung Research, Berlin, Germany.
مؤلفون مشاركون: VX18-445-109 study group
المصدر: The Lancet. Respiratory medicine [Lancet Respir Med] 2022 Mar; Vol. 10 (3), pp. 267-277. Date of Electronic Publication: 2021 Dec 20.
نوع المنشور: Clinical Trial, Phase III; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: England NLM ID: 101605555 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2619 (Electronic) Linking ISSN: 22132600 NLM ISO Abbreviation: Lancet Respir Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Kidlington, Oxford Elsevier, [2013]-
مواضيع طبية MeSH: Cystic Fibrosis*/drug therapy , Cystic Fibrosis*/genetics, Aminophenols/therapeutic use ; Benzodioxoles/therapeutic use ; Child ; Chloride Channel Agonists/therapeutic use ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Double-Blind Method ; Humans ; Indoles ; Mutation ; Pyrazoles ; Pyridines ; Pyrrolidines ; Quality of Life ; Quinolones
مستخلص: Background: Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation.
Methods: We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV 1 of 40-90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV 1 , age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV 1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972.
Findings: Between Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (-1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], p<0·0001), the mean percent predicted FEV 1 increased by 11·2 percentage points (95% CI 9·8 to 12·6) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·0 percentage points (-0·4 to 2·4) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 10·2 percentage points [8·2 to 12·1], p<0·0001), and the mean sweat chloride concentration decreased by 46·2 mmol/L (95% CI 43·7 to 48·7) in the elexacaftor plus tezacaftor plus ivacaftor group and by 3·4 mmol/L (1·0 to 5·8) in the tezacaftor plus ivacaftor group (least squares mean treatment difference -42·8 mmol/L [-46·2 to -39·3], nominal p<0·0001). Most participants (70 [80%] in the elexacaftor plus tezacaftor plus ivacaftor group and 74 [84%] in the tezacaftor plus ivacaftor group) had adverse events that were mild or moderate in severity; serious adverse events occurred in five (6%) of 87 participants in the elexacaftor plus tezacaftor plus ivacaftor group and 14 (16%) of 88 participants in the tezacaftor plus ivacaftor group. One (1%) participant in the elexacaftor plus tezacaftor plus ivacaftor group discontinued treatment due to an adverse event of anxiety and depression. Two (2%) participants in the tezacaftor plus ivacaftor group discontinued treatment due to adverse events of psychotic disorder (n=1) and obsessive-compulsive disorder (n=1).
Interpretation: The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population.
Funding: Vertex Pharmaceuticals.
Competing Interests: Declaration of interests SS received personal fees from Proteostasis Therapeutics, Novartis Pharma, Vertex Pharmaceuticals, Chiesi, and Teva outside of the submitted work; and grants from Galapagos, Proteostasis Therapeutics, Celtaxsys, Flatley, Vertex Pharmaceuticals, Teva, Chiesi, Boehringer Ingelheim, Corbus Pharmaceuticals, and Ionis Pharmaceuticals outside of the submitted work. EFM received personal fees and grants from Vertex Pharmaceuticals during the conduct of the study; personal fees from Roche Pharmaceuticals, Insmed, and Janssen Pharmaceuticals; and other financial support from A Menarini outside of the submitted work. DGD received non-financial support from Vertex Pharmaceuticals during the conduct of the study; personal fees from Vertex Pharmaceuticals, Proteostasis, and Chiesi; and grants from Chiesi outside of the submitted work. JD received advisory board and speaker fees from Vertex Pharmaceuticals outside of the submitted work. EVB received institutional grants from Vertex Pharmaceuticals for the submitted work; and institutional grants from Vertex Pharmaceuticals, Galapagos, and Abbvie for other cystic fibrosis-related trials. MAM received personal fees from Vertex Pharmaceuticals during the conduct of the study; grants from Vertex Pharmaceuticals; and personal fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Galapagos, Sterna Biologicals, Enterprise Therapeutics, Kither Biotech, and Antabio outside of the submitted work. ET received grants and non-financial support from Vertex Pharmaceuticals during the conduct of the study; grants from Abbvie, Boehringer Ingelheim, Bayer, Spyryx, Horizon, Corbus, and Celtaxis; personal fees from Proteostasis and Horizon; and non-financial support from Proteostasis and Spyryx outside of the submitted work. CEW received institutional grants from Vertex Pharmaceuticals during the conduct of the study; grants from Novo Nordisk outside of the submitted work; and personal fees from Vertex Pharmaceuticals, Boehringer Ingelheim, Novartis, DKBmed, Gilead, and In Vivo Academy outside of the submitted work. DWal and SMM have pending patents for methods of treatment for cystic fibrosis, pharmaceutical compositions for treatment of cystic fibrosis, compositions and methods for treatment of cystic fibrosis, and crystalline forms and compositions of CFTR modulators. DWal and SMM have issued patents for crystalline forms and compositions of CFTR modulators. NA, BGB, CH, APL, YL, SMM, ST, JY, and DWal are employees of Vertex Pharmaceuticals and might own stock or stock options in the company. GM and DWat declare no competing interests.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
فهرسة مساهمة: Investigator: P Aurora; S Verhulst; D Watson; M Lorenz; J Roehmel; W Gleiber; S Naehrig; F Stehling; S Sutharsan; S van Koningsbruggen-Rietschel; R Fischer; D Downey; C Haworth; J Duckers; J Legg; P Barry; R Thursfield; SJ Doe; T Hilliard; G MacGregor; EF Nash; NJ Withers; D Peckham; HL Barr; T Lee; R Gray; F Vermeulen; E Van Braeckel; E Vanderhelst; PJ Robinson; CE Wainwright; DJ Smith; SA Mulrennan; BS Clements; P Wark
سلسلة جزيئية: ClinicalTrials.gov NCT04105972
المشرفين على المادة: 0 (Aminophenols)
0 (Benzodioxoles)
0 (CFTR protein, human)
0 (Chloride Channel Agonists)
0 (Indoles)
0 (Pyrazoles)
0 (Pyridines)
0 (Pyrrolidines)
0 (Quinolones)
0 (tezacaftor)
126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
1Y740ILL1Z (ivacaftor)
RRN67GMB0V (elexacaftor)
تواريخ الأحداث: Date Created: 20211223 Date Completed: 20220321 Latest Revision: 20220321
رمز التحديث: 20240628
DOI: 10.1016/S2213-2600(21)00454-9
PMID: 34942085
قاعدة البيانات: MEDLINE
الوصف
تدمد:2213-2619
DOI:10.1016/S2213-2600(21)00454-9